Preferential Targeting of Disseminated Liver Tumors Using a Recombinant Adeno-Associated Viral Vector
| Autor: | Amit C. Nathwani, Mark F. Lythgoe, Marco Della Peruta, Devhrut Nathwani, Erik Årstad, Cecilia Rosales, Eva Galante, Adam Badar, Shilpa Chokshi, Ran Yan, Roger Williams, Azadeh Kia, Andrew M. Davidoff |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Carcinoma Hepatocellular Transplantation Heterotopic Genetic Vectors Mice SCID Gene delivery Thymidine Kinase Viral vector Mice Viral Proteins Transduction (genetics) Capsid Genetics Animals Humans Simplexvirus Medicine Tissue Distribution Promoter Regions Genetic Molecular Biology Research Articles Regulation of gene expression Mice Inbred BALB C business.industry Liver Neoplasms Genetic Therapy Dependovirus Suicide gene Virology Recombinant Proteins Transplantation Disease Models Animal MicroRNAs Gene Expression Regulation Liver Systemic administration Molecular Medicine Expression cassette Genetic Engineering business |
| Zdroj: | Human Gene Therapy. 26:94-103 |
| ISSN: | 1557-7422 1043-0342 |
| DOI: | 10.1089/hum.2014.052 |
| Popis: | A novel selectively targeting gene delivery approach has been developed for advanced hepatocellular carcinoma (HCC), a leading cause of cancer mortality whose prognosis remains poor. We combine the strong liver tropism of serotype-8 capsid-pseudotyped adeno-associated viral vectors (AAV8) with a liver-specific promoter (HLP) and microRNA-122a (miR-122a)-mediated posttranscriptional regulation. Systemic administration of our AAV8 construct resulted in preferential transduction of the liver and encouragingly of HCC at heterotopic sites, a finding that could be exploited to target disseminated disease. Tumor selectivity was enhanced by inclusion of miR-122a-binding sequences (ssAAV8-HLP-TK-122aT4) in the expression cassette, resulting in abrogation of transgene expression in normal murine liver but not in HCC. Systemic administration of our tumor-selective vector encoding herpes simplex virus-thymidine kinase (TK) suicide gene resulted in a sevenfold reduction in HCC growth in a syngeneic murine model without toxicity. In summary, we have developed a systemically deliverable gene transfer approach that enables high-level expression of therapeutic genes in HCC but not normal tissues, thus improving the prospects of safe and effective treatment for advanced HCC. |
| Databáze: | OpenAIRE |
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